Soft gelatin capsules or softgels are predominantly used to contain liquids wherein the active ingredients are present in the dissolved or suspended state. Filled one-piece softgels have been widely known and used for many years and for a variety of purposes. Because softgels have properties that are quite different from telescoping two-piece, hard shell capsules, the softgels are capable of retaining a liquid fill material. Softgels are often used to encapsulate consumable materials, including vitamins, dietary supplements, pharmaceuticals, and the like, in a liquid vehicle or carrier.
A particularly good bioavailability of a pharmacologically active substance is attained if the active substance is successfully dissolved in a suitable solvent and the encapsulated solution is administered to the patient. Producing highly concentrated solutions of any acidic, amphoteric or basic pharmaceutical compound is useful because it permits encapsulation in a softgel capsule of a unit dose which is small enough to permit easy swallowing. Filling a unit dose in a small softgel capsule to permit easy swallowing is useful because it increases patient acceptance of the medication. Patient acceptance of a medication is important because it is a substantial step towards solving the problem of patient noncompliance with the prescribed regimen.
Another utility of highly concentrated solutions is enhancement of bioavailability of the dissolved pharmaceutical compound or composition. Enhanced bioavailability occurs as a result of delivering the pharmaceutical already in solution at the site of absorption, thereby permitting faster and more uniform absorption to occur.
One problem associated with such compositions is that obtaining an appropriate solution of the pharmaceutical composition is sometimes difficult. Often it is not possible to dissolve the pharmaceutical compound in a volume of solvent small enough to produce a softgel which is appropriate in size from the standpoint of economics and patient acceptance. Furthermore, the solvent, carrier or vehicle itself must have sufficient solvating power to dissolve the desired amount of the pharmaceutical compound to produce a highly concentrated solution, while at the same time not hydrolyzing, dissolving or discoloring the capsule shell.
One approach to achieve this desired goal has been the use of enhanced solubility systems such as those described in Yu et al. U.S. Pat. No. 5,071,643. Yu et al. disclose soft gelatin capsules containing highly concentrated acetaminophen solutions comprising 25–40% by weight acetaminophen, hydroxide ions (e.g., potassium hydroxide), water, and polyethylene glycol. However, hydroxide ion sources at levels required to solubilize acetaminophen increase the pH of the solution to the extent that degradation of the softgel capsule occurs.
Other approaches to enhance the solubility of acetaminophen have been used as well. Shelley et al. U.S. Pat. No. 5,505,961 describes a method of increasing the solubility of acetaminophen alone or in combination with antihistamines, antitussives, desongestants, and expectorants to form clear solutions for encapsulation in softgel capsules. Shelley et al. teach compositions comprising acetaminophen, potassium or sodium acetate, polyethylene glycol and polyvinyl pyrrolidone which permits a 325 mg dose to be administered in the same size softgel as a 250 mg dosage product. The capsule sizes needed for a desired dose of these formulations, however, are still relatively large. Another drawback is that the acetate solvent system restricts the amount of other active compounds which can be used due to solubility limitations. Furthermore, the presence of acetate can adversely affect tolerance of certain analgesics.
There exists a need for improved softgel formulations containing pharmaceutical compounds such as acetaminophen which permit high concentrations of the drug to be solubilized in lower fill volumes thereby permitting the desired effective dose of drug to be administered to a patient using smaller capsule sizes.